Impact of nirogacestat on pain, a key symptom in patients with desmoid tumors (DT): Results from the phase 3 DeFi study.
Authors: Winette T.A. Van Der Graaf, Mrinal M. Gounder, Ravin Ratan, Cristina Ivanescu, James Marcus, Timothy Bell, Allison Lim, L. Mary Smith, Ana Belen Oton, Thierry Alcindor, Patrick Schöffski, Breelyn A. Wilky, Richard F. Riedel, Charlotte Benson, Nam Bui, Rashmi Chugh, Shivaani Kummar, Bernd Kasper
Journal: Journal of Clinical Oncology (2023)

11564 Background: Pain reduction is a key treatment goal in DT (aggressive fibromatosis): 60% of patients (pts) experience chronic pain. In the phase 3 DeFi trial, nirogacestat (NIRO; n = 70) significantly improved progression-free survival compared with placebo (PBO; n = 72) in pts with progressing DT (HR: 0.29 [95% CI, 0.15–0.55]; P&lt; 0.001). Also as previously reported, NIRO significantly reduced pain severity by 1.50 points (on a 10-point scale) compared with PBO at cycle 10 (28-day cycles; P&lt; 0.001) per the prespecified secondary endpoint of “worst pain” from the Brief Pain Inventory Short Form (BPI-SF). Additional aspects of pain were collected in DeFi to further characterize treatment impact and consistency across multiple pain assessment tools. Methods: In DeFi, pts completed 3 prespecified pain assessment tools through end of treatment: BPI-SF (worst pain), GOunder/Desmoid Tumor Research Foundation DEsmoid Symptom Scale (GODDESS-DTSS pain scale: worst pain, dull pain, shooting pain), European Organisation for Research and Treatment of Cancer Core Quality of Life Questionnaire (QLQ-C30 pain scale: pain, pain interference with daily activities). Change from baseline (BL) in pain scores was compared between arms; analyses included mixed models for repeated measures to compare change from BL and stratified Cochran-Mantel-Haenszel to compare proportions of pts with clinically meaningful pain reduction (defined using prespecified thresholds) at cycle 10. Cycle 10 was preselected to allow adequate time for a treatment effect to be observed. Results: Statistically significant and clinically meaningful pain reductions were observed with NIRO compared with PBO at cycle 10 across all assessment tools; statistically significant differences between arms occurred as early as cycle 2 and were sustained throughout treatment. At cycle 10, NIRO reduced mean BL pain per GODDESS-DTSS (0–10 range) by 1.78 points (SE = 0.26) and PBO increased pain by 0.32 points (SE = 0.27; P&lt; 0.001). At cycle 10, NIRO reduced mean BL pain per QLQ-C30 (0–100 range) by 22.05 points (SE = 3.38) and PBO increased pain by 7.19 points (SE = 3.64; P&lt; 0.001). Clinically meaningful pain reduction (by ≥2.0 points) per BPI-SF worst pain (0–10 range) was achieved by 72% of pts with NIRO vs 29% of pts with PBO at cycle 10 ( P&lt; 0.001). Per GODDESS-DTSS, clinically meaningful pain reduction (by ≥1.9 points) was achieved by 62% of pts with NIRO vs 19% of pts with PBO at cycle 10 ( P= 0.002). Conclusions: Rapid, sustained, and consistent reductions in different aspects of pain were observed with NIRO compared with PBO across multiple assessment tools in pts with DT. Furthermore, a significantly greater proportion of pts achieved clinically meaningful reductions in pain with NIRO than with PBO. As pain is the most commonly reported symptom, pain reduction should be a key clinical trial endpoint and a key treatment goal in DT. Clinical trial information: NCT03785964 .